PROJECT SUMMARY This application is an ancillary study to the NASH Clinical Research Network (NASH CRN) which has conducted several important clinical studies including landmark clinical trials. However, the studies conducted by the NASH CRN have systematically excluded individuals with HIV infection as their liver disease is thought to be distinct from general population due to ongoing HIV infection, antiretroviral therapy, and concomitant medications and recurrent infections. This exclusion of HIV infected persons led to a large knowledge gap related to fatty liver disease in this population. Recent cross-sectional studies have shown that there is high prevalence of fatty liver disease in HIV infected adults and importantly their risk for advanced fibrosis may be significantly higher than the general population. In order to address the critical knowledge gaps plaguing the field of NAFLD and NASH in HIV, we are proposing the following broad specific aims in our R01 application in response to the PAR-18-042. Specific Aim 1: To examine the prevalence of hepatic steatosis in a cross- sectional study on large cohort of HIV infected individuals. This cross-sectional study will identify both non- genetic and genetic risk factors associated with hepatic steatosis in HIV infected individuals. A robust biobank consisting of plasma, serum, genomic DNA, PBMC, stool and urine will be established. All participants will have (a) liver biochemistries; (b) VCTE; and (c) plasma and genomic DNA collected. Specific Aim 2: To conduct a prospective observational study of 400 HIV infected individuals with histologically characterized NAFLD. Participants in this HIV-NAFLD cohort will be compared to non-HIV infected individuals with NAFLD in the ongoing NASH CRN adult database 2 (DB2) studies for baseline clinical characteristics and demographic, anthropometric, metabolic and cardiovascular risks. Participants will be followed longitudinally on an annual basis according to a scheduling mimicking the DB2 protocol. Specific Aim 3: To carefully characterize liver histology in HIV infected individuals with biopsy proven NAFLD. Key objectives of this aim are (a) to validate the widely used NASH CRN histological scoring system and European SAF scoring systems in population of persons with both HIV and NAFLD and (b) to assess histological similarities and dissimilarities in liver histology between HIV infected and non-infected individuals with NAFLD. NASH CRN Pathology Subcommittee will review liver biopsies from HIV infected individuals. Specific Aim 4: To conduct a multicenter, randomized, double-blind, placebo-controlled, clinical trial of a novel PPAR?/? agonist in 160 HIV infected individuals with biopsy proven NASH. Primary end point will be resolution of NASH with key secondary endpoints being (a) improvement in NAS by 2 points; (b) improvement in fibrosis; (c) improvement in aminotransferases; (d) improvement in cardiovascular risks; and (e) safety and tolerability.